The Impact of the Receptor of Hyaluronan-Mediated Motility (RHAMM) on Human Urothelial Transitional Cell Cancer of the Bladder

Abstract

Hyaluronan (HA) is a carbohydrate of the extracellular matrix with tumor promoting effects in a variety of cancers. The present study addressed the role of HA matrix for progression and prognosis of human bladder cancer by studying the expression and function of HA-related genes.MethodsTissue samples of 120 patients with different stages of transitional cell bladder cancer, who underwent surgical treatment for bladder cancer at the University Hospital of Essen were analysed. mRNA-expression levels of HA synthases (HAS1-3) and HA-receptors (RHAMM and CD44) were evaluated by real time RT-PCR in comparison to healthy bladder tissue as control. In uni- and multivariate cox proportional hazard survival regression analysis, the impact of the gene expression levels on survival was assessed. In vitro knock-down of RHAMM, CD44 and HAS isoenzymes was achieved by siRNA and lentiviral shRNA in J82 bladder cancer cells. Transfected cells were analysed in vitro with regard to proliferation, cell cycle and apoptosis. J82 cells after knock-down of RHAMM were xenografted into male nu/nu athymic mice to monitor tumor progression in vivo.ResultsIn invasive tumor stages RHAMM-, HAS1 and HAS2 mRNA-expression levels were elevated whereas HAS3v1 was reduced as compared to non-invasive tumors. Subsequently, Kaplan-Meier analysis revealed reduced bladder cancer specific survival in patients with high RHAMM mRNA and low HAS3v1 expression. Elevated RHAMM in invasive tumors was confirmed by RHAMM immunohistochemistry. Furthermore, multivariate analysis revealed that only RHAMM expression was associated with poor prognosis independent from other survival factors (HR=2.389, 95% CI 1.227-4.651, p=0.01). Lentiviral RHAMM knock-down revealed reduced J82 cell proliferation in vitro and reduced xenograft tumor growth in vivo.ConclusionThe data suggest that RHAMM plays a crucial role in mediating progression of muscle-invasive bladder cancer and recommends RHAMM for further evaluation as a prognostic marker or therapeutic target in bladder cancer therapy.

Expression patterns of CD168 correlate with the stage and grade of squamous cell carcinoma of head and neck

“…breast, stomach or colorectal cancers, and in multiple myelomas. A previous CD168 knockdown study demonstrated growth reduction of transplanted tumors (28). Increased CD168 expression was revealed to be indicative of an elevated, or abnormal, level of cell proliferation in human OSCC (17).…”

HAS3 underexpression as an indicator of poor prognosis in patients with urothelial carcinoma of the upper urinary tract and urinary bladder

“…Hyaluronan synthase 3 (HAS3) is one of the three HAS isoforms producing HA. HAS3 had been investigated in many cancers [16][17][18][19][20][21]38]. No study, however, has found consistent results of HAS3 effects on different cancer types.…”

“…3 Kaplan-Meier plots demonstrates the prognostic significances of HAS3 immunoexpression for diseasespecific survival and metastasisfree survival in UTUC (a, b) and UBUC (c, d), respectively growth or to overexpression in cancer compared to a normal organ [16,17,[19][20][21]. Contrariwise, other research has suggested that HAS3 is significantly reduced in premalignancy or malignancy compared to its benign counterparts [18,38]. In the present study, HAS3 underexpression was significantly associated with adverse clinicopathological parameters, i.e., higher pT status, nodal metastasis, high histological grade, vascular invasion, and frequent mitoses in both UTUCs and UBUCs.…”

“…HAS3 underexpression not only predicted poorer DSS and MeFS in univariate analysis, but also indicated dismal DSS and MeFS in multivariate analysis. The only study focusing on the expression of HA, its synthases (HAS1-3) and receptors (RHAMM and CD44) in bladder cancer used quantitative real-time RT-PCR, finding that in 120 UBUC patients whose HAS3 transcriptional level was elevated in all bladder cancers compared to healthy bladder tissue, but that it decreased stepwise with increased tumor staging of statistical significance (p<0.001) [38]. Similarly, HAS3 mRNA was also significantly downregulated in tumors with higher tumor grade (p<0.001) and with lymph node metastasis (p=0.046) [38].…”

“…The only study focusing on the expression of HA, its synthases (HAS1-3) and receptors (RHAMM and CD44) in bladder cancer used quantitative real-time RT-PCR, finding that in 120 UBUC patients whose HAS3 transcriptional level was elevated in all bladder cancers compared to healthy bladder tissue, but that it decreased stepwise with increased tumor staging of statistical significance (p<0.001) [38]. Similarly, HAS3 mRNA was also significantly downregulated in tumors with higher tumor grade (p<0.001) and with lymph node metastasis (p=0.046) [38]. In contrast, HAS1 and HAS2 transcripts were significantly upregulated in muscle-invasive tumors and in highgrade tumors [38].…”